A systematic review of antimicrobial resistance in Salmonella enterica serovar Typhi, the etiological agent of typhoid

Abstract

Background: The temporal and spatial change in trends of antimicrobial resistance (AMR) in typhoid have not been systematically studied, and such information will be critical for defining intervention, as well as planning sustainable prevention strategies.

Methodology and findings: To identify the phenotypic trends in AMR, 13,833 individual S. Typhi isolates, reported from 1973 to 2018 in 62 publications, were analysed to determine the AMR preponderance over time. Separate analyses of molecular resistance determinants present in over 4,000 isolates reported in 61 publications were also conducted. Multi-drug resistant (MDR) typhoid is in decline in Asia in a setting of high fluoroquinolone resistance while it is on the increase in Africa. Mutations in QRDRs in gyrA (S83F, D87N) and parC (S80I) are the most common mechanisms responsible for fluoroquinolone resistance. Cephalosporin resistant S. Typhi, dubbed extensively drug-resistant (XDR) is a real threat and underscores the urgency in deploying the Vi-conjugate vaccines.

Conclusion: From these observations, it appears that AMR in S. Typhi will continue to emerge leading to treatment failure, changes in antimicrobial policy and further resistance developing in S. Typhi isolates and other Gram-negative bacteria in endemic regions. The deployment of typhoid conjugate vaccines to control the disease in endemic regions may be the best defence.

Fig 1. Search strategy and PRISMA flow-diagram.

Fig 2

Antimicrobial non-susceptible trends of S. Typhi over time A) Global trends, B) Trends in Asia C) Trends in Africa. Fig 2A is Graphical representation of the proportion of S. Typhi isolates obtained from reports that were resistant to antimicrobials (indicated by coloured lines). Isolates represented in this graph were consolidated from published reports between 1973 and 2017 from endemic and epidemic sources, assembled systematically. In comparison to Fig 2A, Fig 2B represents the AMR trends obtained from Asian reports. Note the similarity in the trend between 2a and 2b; it is evident that non-susceptibility to first-line antimicrobials (chloramphenicol, co-trimoxazole and ampicillin) has decreased over time. Fig 2C represents the AMR trends from African reports. MDR Typhoid is widely prevalent while fluoroquinolone resistance is low.

Fig 3. Summary of the molecular determinants of resistance in S. Typhi as identified in this review.

Panel A is a graphical representation of MDR genes and plasmids with the frequency of each inset as a matrix indicating the resistance gene and corresponding antimicrobial. The arrow indicates the arrangement of MDR genes in the plasmid or the location within the bacterial genome. Panel B illustrates the proportion of isolates harbouring fluoroquinolone proportion of isolates derived from the 4 main South Asia countries. resistance determining SNPs and the regions of origin of isolates, the vertical arrow indicates to the graph illustrating the proportion of isolates retrieved from each region and the horizontal arrow points to the graph depicting the proportion of isolates from each of the South Asian countries. Fluoroquinolone resistance occurs through mutations DNA gyrase enzyme of the bacteria which is encoded by gyrA, parC and parE as mentioned in the matrix inset.—SNP–Single Nucleotide Polymorphism- Amino acid abbreviations S–Serine, F- Phenylalanine, Y–Tyrosine, D–Aspargine, N–Aspartic acid, I–Isoleucine.